Process for the preparation of 1,5-dideoxy-1, 5-imino hexitols from oximes or imines

ABSTRACT

A process for the preparation of 1,5-dideoxy-1,5-imino hexitols of a hexose sugars from novel hydroxyl protected oxime intermediates. The process includes formation of a lactam which is reduced to the hexitol. The hexitols are useful as drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Provisional Application No.60/193,554, filed Mar. 31, 2000.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] None.

BACKGROUND OF THE INVENTION

[0003] (1) Field of the Invention

[0004] The present invention relates to multistep synthesis of a1,5-dideoxy-1,5-imino hexitol from a ketoaldonic acid methyl ester of ahexose sugar with protected hydroxyl groups and to novel intermediates.In particular the present invention relates to processes which enablethe production of novel intermediates to the hexitol and in particular,a ketoaldonic acid methyl ester oxime or alkylimine, which forms thering structure of the hexitol by alternate routes.

[0005] (2) Description of Related art

[0006] Over the last three decades there has been a continued interestin natural and synthetic imino-sugars because of their high potency asglycosidase inhibitors ((a) Grabner, R. W., et al., U.S. Pat. No.5,695,969; (b) Boshagen, H., et al., U.S. Pat. No. 4,940,705; (c)Shilvock, J. P., et al., Tetrahedron Lett., 37 8569-8572 (1996); (d)Rajanikanth, D. B., et al., J. Chem. Soc. Perkin Trans. I 2151-2152(1992); (e) Hussain, A., et al., Tetrahedron, 49 2123-2130 (1993); (f)Defoin, A., et al., Tetrahedron Lett. 34 4327-4330) (1997); (g) Defoin,A., et al., Tetrahedron 53 13769-13782 (1997); (h) Defoin, A., et al.,Tetrahedron Lett. 35 5653-5656 (1994); (i) Fleet, G. W. J., et al.,Tetrahedron lett. 29 2871-2874 (1988); (j) Fleet, G. W. J., et al.,Tetrahedron 45 327-336 (1989); (k) Takahashi, S., et al. Chem. Lett.21-24 (1992); (1) Takahashi, S., et al., J. Chem. Soc., Perkin Trans. I,607-612 (1997); (m) Hendry, D., et al., Tetrahedron Lett. 28 4597-4600(1987); (n) Hendry, D., et al., Tetrahedron Lett. 28 4601-4604 (1987);(o) Straub, A., et al., J. Org. Chem. 55 3926-3932 (1990); Delinck, D.L., et al., Tetrahedron Lett. 31 3093-3096 (1990); (r) Look, G. C., etal., Acc. Chem. Res. 26 182-190 (1993); (s) Kajimoto, T., et al., J. Am.Chem. Soc. 113 6678-6680 (1991)). Glycosidases catalyze the hydrolysisof glycosidic linkages and are the key enzymes in the degradation ofcomplex carbohydrates. One of their main metabolic roles is theconversion of complex non-absorbable carbohydrates into absorbable mono-or oligosaccharides (Truscheit, E., et al., Angew. Chem. Int. Ed. Engl.20 744-761 (1981)). The rapid action of these enzymes can lead, however,to undesirable elevations in blood glucose in diabetes. Iminosugars havebeen shown to act as glycosidase inhibitors and to retard and regulatethe intestinal carbohydrate digestion. They are therefore excellent drugcandidates for diabetes therapy (Liu, P. S., U.S. Pat. No. 4,634,765(1987)). An even more exciting potential use of iminosugars is in thetreatment of cancer and viral diseases (Rohrschneider, L. R., et al.,U.S. Pat. No. 4,837,237 (1989)). It has been shown that modification ofoligosaccharide structures may alter metastatic capacity of cancer cellsand 1,5-diimino-1,5-dideoxyglucitol (deoxynojirimycin) (1) (Tsuruoka,T., et al., U.S. Pat. No. 5,250,545 (1993)) swainsonine (2) (Dennis, J.W., Cancer Res. 46 5131-5136 (1986)) and castanospermine (3) (Humphries,M. J., et al., Cancer Res. 46 5215-5222 (1986)) (FIG. 1.) can markedlyinhibit metastasis of cancer cells. They might, therefore, be used forthe effective treatment of cancer.

[0007] N-Butyl-deoxynojirimyciin shows excellent activity against herpesvirus (Jacob, G. S., et al., U.S. Pat. No. 4,957,926 (1990)) whilsthaving low cyto-toxicity and no inhibitory effect on the growth ofnormal cells. The greatest prospect for the use of iminosugars as drugsis probably for the treatment of AIDS. Glycosidase inhibitors preventthe processing of N-linked complex oligosaccharides. This results in thedisruption of the synthesis of viral coat glycoproteins such as thecritical one called gp120. This supposedly leads to the loss ofrecognition by the CD-4 receptor of the target cell with concomitantreduction of syncytia formation resulting in the reduction of virusinfectivity and the inhibition of viral replication (Walker, B. D., etal., Proc. Natl. Acad. Sci. USA 84 8120-8124 (1987); Karpas, A., et al.,Proc. Natl. Acad. Sci. USA 85 9229-9233 (1988); Fleet, G. W. J., et al.,FEBS Lett. 237 128-132 (1988)). Clinical trials have been launched forN-Butyl-deoxynojirimycin (Rohrschneider, L. R., U.S. Pat. No. 5,643,888(1997)). The iminosugars that have been the most investigated aredeoxynojirimycin ((a) Schroder, T., et al., U.S. Pat. No. 4,806,650(1989); (b) Koebernick, W., U.S. Pat. No. 4,611,058 (1986); (c)Anzeveno, P.B., et al. U.S. Pat. No. 5,227,479 (1993); (d) Anzeveno,U.S. Pat. No. 4,908,439 (1990); (e) Tsuda, Y., et al., Heterocycles, 2763-66 (1988); (f) Inouye, S., et al., Tetrahedron 23 2125-2144 (1968);(g) Vasella, A., et al., Helv. Chim. Acta 65 1134-1144 (1982); Ikota,N., et al., Heterocycles 46 637-643 (1997); (i) Paulsen, H., et al.,Chem. Ber 100 802-815 (1967); (j) Rudge, A. J., et al., Angew. Chem.Int. Ed. Engl. 33 2320-2322 (1994); (k) Behling, J., et al., Synth.Commun. 21 1383-1386 (1991); (1) Kinast, G., et al., Angew. Chem. Int.Ed. Engl. 20 805-806 (1981); (m) Pederson, R. L., et al., TetrahedronLett. 29 4645-4648 (1988); (n) Osten, C. H., et al., J. Am. Chem. Soc.111 3924-3927 (1989)) and its N-alkyl analogues (Grabner, R. W., et al.,U.S. Pat. No. 5,610,039 (1997); U.S. Pat. No. 4,806,650; U.S. Pat. No.4,611,058; U.S. Pat. No. 4,940,705).

[0008] The chemical synthesis of nojirimycin derivatives are generallytoo involved and not suitable for commercial applications. Thechemo-microbiological method patented by Grabner (U.S. Pat. No.5,695,969; U.S. Pat. No. 5,610,039)) provides an elegant method fortransforming a sugar into its imino-derivative by reductive animation ofa 5-keto aldose obtained by bacterial oxidation of glucose. The methodis in particular however, not applicable to the D-galacto derivatives ofthe present invention.

[0009] Other related patents are: U.S. Pat. Nos. 5,227,479, 5,250,545,5,695,969, 4,957,926, 4,908,439 and 4,634,765.

SUMMARY OF INVENTION

[0010] The present invention relates to a process for the preparation ofan aldonic -5-oxime methyl ester of a hexose sugar which has protectedhydroxyl groups which comprises:

[0011] (a) reacting a ketoaldonic acid methyl ester of the sugar withthe protected hydroxyl groups with a an alkylamine or hydroxylamine acidsalt in an organic solvent with a tertiary amine to react with an acidgenerated in the reaction at a temperature of about 60° C. or less toproduce the oxime methyl ester in a reaction mixture; and

[0012] (b) separating the oxime methyl ester from the reaction mixture.

[0013] The present invention also relates to a a process for thepreparation of methyl 2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oximewhich comprises:

[0014] (a) reacting methyl 2,3,4,6 tetra-O-acetyl-5-hexulosonic acidmethyl ester with hydroxylamine hydrochloride in a first organic solventwith a tertiary amine to react with an acid generated in the reactionmixture at a temperature of between about −10 and 60° C.;

[0015] (b) introducing the reaction mixture into water containing ice;

[0016] (c) extracting the oxime from the reaction mixture with a secondorganic solvent for the oxime; and

[0017] (d) separating the oxime from the second solvent.

[0018] Further, the present invention relates to a process for thepreparation of an aldonic acid hydrazide oxime of a hexose sugar withprotected hydroxyl groups which comprises:

[0019] (a) reacting an aldonic acid-5-oxime or alkylimine methyl esterof the sugar with the protected hydroxyl groups with anhydrous hydrazinein an organic solvent at less than about 30° C. to produce the hydrazideoxime; and

[0020] (b) separating the hydrazide oxime of the sugar from the reactionmixture.

[0021] The present invention also relates to a process for thepreparation of the 5-lactam of a hexose sugar which has hydroxyl groupswhich comprises:

[0022] (a) reacting an aldonic acid methyl ester oxime or alkylimine ofthe sugar with the protected hydroxyl groups with hydrogen and ahydrogenation catalyst in an acidic solvent at a temperature betweenabout 20 and 80° C. and at a pressure between about 200 and 400 psi ofthe hydrogen to produce the acid lactam of the sugar in a reactionmixture; and

[0023] (b) separating the lactam from the mixture.

[0024] The present invention also relates to a process for thepreparation of a 1,5-imino-1,5-dideoxyhexitol which comprises:

[0025] (a) reacting a 5-imino-5-deoxyhexonic acid lactam of a hexosesugar which has hydroxyl groups with a reducing agent in a solvent at atemperature between about 0° and 80° C. to produce the1,5-imino-1,5-dideoxyhexitol in a reaction mixture; and

[0026] (b) separating the imino 1,5-imino-1,5-dideoxyhexitol from thereaction mixture.

[0027] The present invention also relates to a process for thepreparation of 1,5-imino,-1,5-dideoxy hexitol with or without theprotected hydroxyl groups which comprises:

[0028] (a) reacting an acid ester or a hydrazide of a 5-hexulosonic acidoxime or alkylimine with or without the protected hydroxyl group withhydrogen and a hydrogenation catalyst in an acidic solvent at atemperature between about 20 and 80° C. and a pressure between about 200and 400 psi to form a 5-imino-5-deoxyaldonic acid lactam; and

[0029] (b) reducing, if necessary deprotecting the hydroxyl groups, thelactam with a reducing agent to form the 1,5-dideoxy-1,5-imino hexitol.

[0030] The present invention relates to a process for the preparation of1,5-imino,-1,5-6-trideoxy hexitol as a product which comprises:

[0031] (a) reacting methyl-2,3,4,6-tetra-O-acetyl-5-hexulosonic acidoxime with hydrogen and a hydrogenation catalyst at a temperaturebetween about 20 and 80° C. and a pressure between about 200 and 400 psiin an acidic solvent to form a 1,5,6-triacetoxy acid lactam;

[0032] (b) reducing and deacetylating the lactam with a reducing agentto form the 1,5-imino hexitol.

[0033] The present invention relates to a process for producing a1,5-imino hexitol which comprises:

[0034] (a) reacting an aldonic acid hydrazine-5-oxime or alkylimine witha reducing agent in an organic solvent at a temperature between about 20and 80° C. to produce the 1,5imino hexitol in a reaction mixture; and

[0035] (b) separating the 1,5-imino hexitol from the reaction mixture.

[0036] The present invention relates tomethyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime;methyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime;tri-O-acetyl-5-amino-5,6-dideoxy-D-gluconic acid lactam;methyl-2,3,4,6-tetra-O-acetyl-L-xylo-5-hexulosonic acid hydrazide oxime;and L-xylo-5-hexulosonic acid hydrazide.

BRIEF DESCRIPTION OF DRAWINGS

[0037]FIG. 1 is a drawing showing the schematic reactions of Examples 1and 2. The numbers are for the structures of the compounds of theseExamples.

[0038]FIG. 2 is a drawing showing the schematic reactions of thereactions of Examples 3 to 6. The numbers are for structures of thecompounds of these Examples.

[0039]FIG. 3 is a drawing showing the reactions where an oxime group isreplaced with an imino alkyl group.

[0040]FIG. 4 is a drawing showing the reaction of the hexitol with analdehyde to produce an alkyl group on the nitrogen.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0041] In particular, the present invention relates tomethyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime 5(FIG. 1) as an intermediate for the synthesis of D-dideoxy galactonojirimycins 7. The present invention provides a method for thepreparation of 1,5-imino-1,5-dideoxy and 1,5,6-triteoxy alditols withthe D-galacto configurations starting from β-glactosides via hexulosonicacid oximes which have not been reported before now. The procedure isespecially valuable because of its high stereoselectivity andstraightforwardness. The key steps are the reduction of the oximederivatives to the lactams which is then further reduced to the targetcompounds. The C6 position can be deoxygenated during the reduction ifit bears an acetoxy group. The trideoxy imino sugars are then produced.Deacetylation prior to oxime reduction gives the dideoxy compounds.

[0042] The present invention provides a simple access toD-galactonojirimycins from the new oxime intermediate methyl2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime 5. The methodalso allows access to the 5-amino-5-deoxy-D-galacturonic acid δ-lactams.This also is not known before now although the gluco-isomer has beenmade by the oxidation of nojirimycin (Kajimoto, T., et al., J. Am. Chem.Soc. 113 6187-6196 (1991)). In this method, the ketoaldonic acid methylester is converted to the previously unreported oxime which is thenreduced to the amine which cyclizes to give the lactam. The lactam isreduced to the imino sugar by borane or a metal hydride reagent. (Scheme1). Despite the formation of both the cis- and trans oximes, noL-derivatives are formed Reduction of the peracetylated oxime leads todeoxygenation of the 6 position to give the tri-deoxydiiminoalditol(dideoxy-D-galacto-nojirimycin 4).

EXAMPLE 1 Methyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acidoxime

[0043]5 The ketoaldonic acid 4 (7g, 18.61 mmol) was dissolved inpyridine (16 ml) and the solution cooled to 0° C. Hydroxylaminehydrochloride (2 g, 28.77 mmol) was then added and the solution stirredat 0° C. for 15 minutes and then for another 2 hours at roomtemperature. The mixture was poured onto ice and water and thenextracted three times with chloroform. The combined chloroform layerswere subsequently washed with water, dried with Na₂SO₄ and thenevaporated. Crystallization from hot ethanol gave white crystals of theoxime (85%) as a mixture of cis-trans isomers: ¹H NMR (CDCl₃) δ isomer1:1.98 (s, 3 H, OAc), 2.01 (s, 3 H, OAc), 2.08 (s, 3 H, OAc), 2.15 (s, 3H, OAc), 3.70 (s, 3H, OCH₃), 4.82 (d, 1H, J_(6a,6b) 14.6 Hz, H6-a), 5.11(d, 1H, H6-b), 5.35 (d, 1H, J_(3,4) 1.9 Hz, H-4), 5.68 (d, 1H, J_(3,2)9.0, Hz, H-2), 5.84 (dd, 1H, H-3); ¹³C NMR (CDCl₃) δ20.2, 20.3, 20.4,20.5, 52.6, 56.4,68.7, 69.2, 69.6, 149.9, 167.5, 168.9, 169.3, 170.0,170.3.

EXAMPLE 2 1,5-imino-1,5, 6-trideoxy-D-galactito(dideoxy-D-galacto)nojirimycin

[0044]7 This was prepared from the oxime 5 (7.4 g, 18.92 mmol) byreduction with hydrogen on palladium in acetic acid. The intermediateamino ester was cyclized to form a lactam 6 that was then reduced byborane. Flash column chromatography using a chloroform-methanol (6:1)mixture gave (dideoxy-D-galacto) nojirimycin 7 (1.5 g, 30%):[α]²³D+27.0° © 1.3, CHCl₃), lit.+49.0° © 1, CHCl₃) [20]; ¹H NMR (D₂O)δ1.21 (d, 3H, J_(5,6) 6.6 Hz, H-6), 2.73 (t, 1H, J_(1a,1e)=J_(1a,2) 11.9Hz, H-1a), 3.30 (dd, 1H, J_(1e,2) 5.4 Hz, H-1e), 3.37 (m, 1H, H-5), 3.50(dd, 1H, J_(2,3) 9.6 Hz, J_(3.4) 3.1 Hz, H-3), 3.90 (d, 1H, J_(4.5) 3.1Hz, H-4), 3.91 (ddd, 1H, H-2); ¹³C NMR (D₂O) δ14.2, 46.1, 55.0,64.4,69.9, 73.1.

[0045] Methyl-2,3,4-6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oximesare intermediates for the preparation of di and tri-deoxynojirimycins.The present invention provides a general method for the preparation of1,5-imino-1,5-6,trideoxy alditols with the D-gluco configurationsstarting from the previously unreportedmethyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime 9 (FIG.2). The key steps are the selective reduction of the oxime derivativesto lactams which are further reduced to the target compounds. The C6position can be deoxygenated during the reduction if it bears an acetoxygroup. The trideoxy imino sugars are then produced. Deacetylation priorto oxime reduction gives the dideoxy compounds.

[0046] The present invention provides a simple access to D-gluconojirimycins from the new oxime intermediateMethyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime. Themethod also allows access to the 5-amino-5-deoxy-D-glucuronic acidδ-lactams. This also is known from the oxidation of nojirimycin(Kajimoto, T., et al., J. Am. Chem. Soc. 113 6187-6196 (1991)). It is anexcellent glycosidase inhibitor at concentrations 100 times lower thanmost of the other inhibitors tested (Kajimoto, T., et al., J. Am. Chem.Soc. 113 6187-6196 (1991)). In the method we describe here theketoaldonic acid methyl ester is converted to the previously unreportedoxime which is then reduced to the amine which cyclizes to give thelactam. The lactam is reduced to the imino sugar by borane or a metalhydride reagent. (Pathway 1). Despite the formation of both the cis- andtrans oximes, no L-derivatives are formed. Reduction of theperacetylated oxime leads to deoxygenation of the 6 position to give thetri-deoxydiiminoalditol (dideoxy-D-gluco-nojirimycin) 14. Access to the6-hydroxy derivatives was readily achieved by deacetylating the oximewith hydrazine prior to reduction. The deacetylation yielded the acylhydrazide in quantitative yield (Pathway 2).

EXAMPLE 3 Methyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime

[0047]9 The ketone 8 (7 g, 18.61 mmol) was dissolved in pyridine (16 ml)and the solution cooled to 0° C. Hydroxylamine hydrochloride (2 g, 28.77mmol) was then added and the solution stirred at 0° C. for 15 minutesand then for another 2 hours at room temperature. The mixture was pouredonto ice and water and then extracted three times with chloroform. Thecombined chloroform layers were subsequently washed with water, driedwith Na₂SO₄ and then evaporated. Crystallization from hot ethanol gavewhite crystals of the oxime 9 (6.9 g, 95%) as a 3:2 mixture of cis-transisomers: Isomer 1: ¹H NMR (CDCl₃) 67 1.93 (s, 3 H, OAc), 1.94 (s, 3 H,OAc), 2.00 (s, 3 H, OAc), 2.01 (s, 3 H, OAc), 3.56 (s, 3 H, OCH₃), 4.36(d, 1H, J_(6a,6b) 12.4 Hz, H6-a), 4.72 (d, 1H, H6-b), 4.99 (d, 1H,J_(3,4) 2.6 Hz, H-4), 5.72 (dd, 1H, J_(3,2) 7.8 Hz, H-3), 6.28 (d, 1H,H-2); ¹³C NMR (CDCl₃) δ20.5, 20.4, 52.8, 61.3, 66.1, 69.5, 69.8, 149.9,167.3, 169.4, 169.5, 170.1; HRMS (M+H⁺) calcd. 392.1193, found 392.1198.Isomer 2: mp=121-122° C; ¹H NMR (CDCl₃) δ1.88 (s, 3 H, OAc), 1.89 (s, 3H, OAc), 1.98 (s, 3 H, OAc), 2.00 (s, 3 H, OAc), 3.56 (s, 3H, OCH₃),4.82 (s, 2H, H-6), 5.16 (d, 1H, J_(3,4) 2.6 Hz, H-4), 5.62 (d, 1H,J_(3,2) 8.5, H-2), 5.78 (dd, 1H, H-3); ¹³C NMR (CDCl₃) δ20.5, 20.4,52.8, 61.3, 66.1, 69.5, 69.8, 149.9, 167.3, 169.4, 169.5, 170.1.

EXAMPLE 4 Tri-O-acetyl-5-amino-5,6-dideoxy-D-gluconic acid lactam

[0048]10 A solution of oxime 9 (6.9, g, 17.64 mmol) in glacial aceticacid (275 ml), containing 10% Pd/C (2.76 g) was hydrogenated in a Parrreactor under a H₂ pressure of 300-400 psi for 40 hours at 55° C. Thereaction mixture was filtered through celite and washed with ethanol.The solvent was rotary-evaporated and the lactam 10 (5 g, 100%) wasobtained as a light yellow syrup: [α]²³ D+70.0° © 1.56, CHCl₃); ¹H NMR(CDCl₃) δ1.11 (d, 3H, J_(5,6) 6.3 Hz, H-6), 1.94 (s, 3 H, OAc), 1.98 (s,3 H, OAc), 2.00 (s, 3 H, OAc), 3.51 (m, 1H, J_(4,5) 9.7, Hz, H-5), 4.94(t, 1H, J_(3,4) 9.7 Hz, H-3), 4.96 (d, 1H, H-2), 5.40 (t, 1H, H-4); ¹³CNMR (CDCl₃) δ18.0, 20.3, 20.3,48.7, 70.6, 70.9, 71.4, 166.7, 169.4,169.6, 169.8; HRMS (M+H⁺) calcd. 288.1083, found 288.1089.

EXAMPLE 5 1,5-imino-1,5,6-trideoxy-D-glucitol

[0049]11 1M BH₃/THF (50 ml, 50 mmol) was added under N₂ to a solution oflactam 10 (5 g, 17.41 mmol) in THF (33 ml). The mixture was stirred atroom temperature for 1.5 hours and then refluxed for another 1.5 hour.After cooling to room temperature 9% methanolic HCl (40 ml) wascarefully added and the resulting solution was refluxed for 30 minutes.The THF was removed by rotary evaporation and the reaction mixture wasdissolved repeatedly in methanol, followed by evaporation to removeborates. Water was added to the dry crude product 10 and the solutionwas passed through an anion exchange resin (Amberlite IR-45 OH-form) andthen dried on the rotary evaporator. To remove the last traces ofborates, a solution of 1M NaOH (15 mol) and methanol (6 ml) were addedto the crude product and the mixture was stirred overnight at roomtemperature. The methanol was evaporated and the aqueous solution waslyophilized. A methanolic HCl solution was added, which precipitatedNaCl while the methanolic solution was dried, to give the product 10(2.43 g, 95%): [α]²³D+15.5° © 1.88, H₂O), lit. +13.° © 1.0, H₂O) [18];¹H NMR (D₂O) δ1.25 (d, 3H, J_(5,6) 6.3 Hz, H-6), 2.77 (dd, 1H, J_(1a,1e)12.4 Hz, J_(1a,2) 11.7 Hz, H-1a), 3.02 (dd, 1H, J_(4,5) 10.0 Hz, H-5),3.23 (dd, 1H, J_(3,4) (dd, 1H, J_(3,4) 9.0 Hz, H-4), 3.33 (dd, 1H,J_(1e,2b) 5.1 Hz, H-1e), 3.31 (dd, 1H, J_(2,3) 9.2 Hz, H-3), 3.63 (ddd,1H, H-2); ¹³C NMR (D₂O) δ17.5, 49.5, 55.2, 71.4, 76.7, 79.0.

EXAMPLE 6 Tetra-O-acetyl-5-amino-5-deoxy-gluconic acid lactam

[0050]13 The acetylated oxime 9 (1.5 g, 3.84 mmol) was deacetylated withconcomitant conversion to the acyl hydrazide by treatment with anhydroushydrazine (0.75 ml, 23.89 mmol) in methanol (15 ml) at room temperaturefor 2 hours. Evaporation of the solvent gave the crude acid hydrazide12: ¹H NMR (D₂O) δ4.18 (1H, dd, J=4.6 Hz, J=7.0 Hz) 4.51 (1H, d, J=6.5Hz), 4.43 (1H, d, J=14.9 Hz), 4.53 (1H, d, J=14.8 Hz), 5.18 (1H, d,J=4.6 Hz); ¹³C NMR (D₂O) δ61.1, 69.1, 73.4, 73.5, 160.7, 173.4. Thishydrazide 12 was hydrogenated in glacial acetic acid with 10%, Pd/C (0.4g) at 50° C. and 300 psi pressure of H₂ for 2 days. After filtrationthrough celite, the solution was dried on the rotary evaporator and thecrude product acetylated with acetic anhydride (15 ml) and pyridine (15ml) for 5 hours at room temperature. The mixture was poured into coldwater and extracted with chloroform. The chloroform layer was dried withNa₂SO₄. Evaporation of the solvent gave crude product 13 (1.47 g), whichwas subjected to flash chromatography on silica (eluenthexane-acetone=2:1) to give the perahydroxy lactam 13 (0.5 g) C-5epimer: mp=177-178° C; [α]²³D+88.6° © 1.11, CHCl₃), lit.+104° © 1.73,CHCl₃) [17]; ¹H NMR (CDCl₃) δ2.03 (s, 3H, OAc), 2.06 (s, 3 H, OAc), 2.08(s, 3 H, OAc), 2.10 (s, 3 H, OAc), 3.75 (ddd, 1H, J_(4,5) 9.7 Hz,J_(5,6a) 2.9 Hz, J_(5,6b) 6.5 Hz, H-5), 3.96 (dd, 1H, J_(6a,6b) 11.7 Hz,H6-b), 4.22 (dd, 1H, H-6a), 5.06 (d, 1H, J_(3,2) 9.5 Hz, H-2), 5.20 (t,1H, J_(3,4) 9.5 Hz, H-3), 5.53 (dd, 1H, H-4), 6.48 (s, 1H, s, NH); ¹³CNMR (CDCl₃) δ20.5, 20.5, 20.5, 20.6, 52.4, 62.7, 67.2, 70.4, 70.5,166.2, 169.4, 169.6, 170.0, 170.4 HRMS (M+H⁺) calcd. 346.1060, found346.1143. Epimer: [α]²³D+3.1° © 1.81, CHCl₃); ¹H NMR (CDCl₃) 1.98 (s, 3H, OAC), 1.99 (s, 3 H, (OAC), 2.00 (2,3 H, OAC), 2.02 (s, 3 H, OAC),3.88 (1H, m, H-5), 4.04 (dd, 1H, J_(6a,6b) 11.4 Hz, J_(5,6b) 6.3 Hz,H6-b), 4.18 (dd, 1H, J_(5,6a) 3.9 Hz, H-6a), 5.15 (dd, 1H, J_(4,5) 9.5Hz, J_(3,4) 7.5 Hz, H-4), 5.15 (d, 1H, J_(2,3) 7.5 Hz, H-2), 5.39 (t,1H, H-3), 7.27 (1H, s, broad, NH); ¹³C NMR (CDCl₃) δ20.2, 20.3, 20.4,50.0, 62.0, 68.0, 69.8, 70.0, 166.7, 169.3, 169.7, 170.3, 170.6. Thelactam 13 was converted to the 1,5-diamino-1,5-dideoxy-D-glucitol(dideoxy-D-gluco)nojuirmycin 14 as in Example 5.

[0051] It will be appreciated that the imino group can contain a loweralkyl group containing 1 to 6 carbon atoms rather than hydrogen. Theoxime group in compound 5 would then be an imino alkyl group, preferablywhere alkyl contains 1 to 8 carbon atoms. The reactions are ahown inFIG. 3. The hydrogen on the hexitol can be replaced with an alkyl groupby reaction with an alkyl aldehyde and a reducing agent as shown in FIG.4.

[0052] It is intended that the foregoing description be onlyillustrative of the present invention and that the present invention belimited only by the hereinafter appended claims.

We claim:
 1. A process for the preparation of an aldonic—5-oxime methylester of a hexose sugar which has protected hydroxyl groups whichcomprises: (a) reacting a ketoaldonic acid methyl ester of the sugarwith the protected hydroxyl groups with a an alkylamine or hydroxylamineacid salt in an organic solvent with a tertiary amine to react with anacid generated in the reaction at a temperature of about 60° C. or lessto produce the oxime methyl ester in a reaction mixture; and (b)separating the oxime methyl ester from the reaction mixture.
 2. Theprocess of claim 1 wherein the sugar has an arabino steroconfiguration.3. The process of claim 1 wherein the sugar has a xylosteroconfiguration.
 4. The process of claim 1 wherein the tertiary amineis pyridine which also acts as the organic solvent for the reaction. 5.The process of claim 1 wherein x is lower alkyl.
 6. The process of claim1 wherein x is hydroxyl.
 7. A process for the preparation of methyl2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oxime which comprises: (a)reacting methyl 2,3,4,6 tetra-O-acetyl-5-hexulosonic acid methyl esterwith hydroxylamine hydrochloride in a first organic solvent with atertiary amine to react with an acid generated in the reaction mixtureat a temperature of between about -10 and 60° C.; (b) introducing thereaction mixture into water containing ice; (c) extracting the oximefrom the reaction mixture with a second organic solvent for the oxime;and (d) separating the oxime from the second solvent.
 8. A process forthe preparation of an aldonic acid hydrazide oxime of a hexose sugarwith protected hydroxyl groups which comprises: (a) reacting an aldonicacid-5-oxime or alkylimine methyl ester of the sugar with the protectedhydroxyl groups with anhydrous hydrazine in an organic solvent at lessthan about 30° C. to produce the hydrazide oxime; and (b) separating thehydrazide oxime of the sugar from the reaction mixture.
 9. The processof claim 8 wherein the sugar has an arabino steroconfiguration.
 10. Theprocess of claim 8 wherein the sugar has a xylo steroconfiguration. 11.The process of claim 8 which is the 5 oxime.
 12. The process of claim 8which is the 5-alkylimine.
 13. A process for the preparation of the5-lactam of a hexose sugar which has hydroxyl groups which comprises:(a) reacting an aldonic acid methyl ester oxime or alkylimine of thesugar with the protected hydroxyl groups with hydrogen and ahydrogenation catalyst in an acidic solvent at a temperature betweenabout 20 and 80° C. and at a pressure between about 200 and 400 psi ofthe hydrogen to produce the acid lactam of the sugar in a reactionmixture; and (b) separating the lactam from the mixture.
 14. The processof claim 13 wherein the ester and lactam have an arabinosteroconfiguration.
 15. The process of claim 13 wherein the lactam has axylo steroconfiguration.
 16. The process of claim 13 which is the5-oxime.
 17. The process of claim 13 which is the 5-alkylimine.
 18. Aprocess for the preparation of a 1,5-imino-1,5-dideoxyhexitol whichcomprises: (a) reacting a 5-imino-5-deoxyhexonic acid lactam of a hexosesugar which has hydroxyl groups with a reducing agent in a solvent at atemperature between about 0° and 80° C. to produce the1,5-imino-1,5-dideoxyhexitol in a reaction mixture; and (b) separatingthe imino 1,5-imino-1,5-dideoxyhexitol from the reaction mixture. 19.The process of claim 18 wherein the ester and lactam have an arabinosteroconfiguration.
 20. The process of claim 18 wherein the lactam has axylo steroconfiguration.
 21. A process for the preparation of1,5-imino,-1,5-dideoxy hexitol with or without the protected hydroxylgroups which comprises: (a) reacting an acid ester or a hydrazide of a5-hexulosonic acid oxime or alkylimine with or without the protectedhydroxyl group with hydrogen and a hydrogenation catalyst in an acidicsolvent at a temperature between about 20 and 80° C. and a pressurebetween about 200 and 400 psi to form a 5-imino-5-deoxyaldonic acidlactam; and (b) reducing, if necessary deprotecting the hydroxyl groups,the lactam with a reducing agent to form the 1,5-dideoxy-1,5-iminohexitol.
 22. The process of claim 21 as the oxime.
 23. The process ofclaim 21 as the alkylimine.
 24. A process for the preparation of1,5-imino,-1,5-6-trideoxy hexitol as a product which comprises: (a)reacting methyl-2,3,4,6-tetra-o-acetyl-5-hexulosonic acid oxime withhydrogen and a hydrogenation catalyst at a temperature between about 20and 80° C. and a pressure between about 200 and 400 psi in an acidicsolvent to form a 1,5,6-triacetoxy acid lactam; (b) reducing anddeacetylating the lactam with a reducing agent to form the 1,5-iminohexitol.
 25. The process of claim 24 wherein the 5-hexulosonic acid isL-xylo and hexitol is D-glucitol.
 26. The process of claim 24 wherein5-hexulosonic acid is L-arabino and hexitol is D-galactitol.
 27. Aprocess for producing a 1,5-imino hexitol which comprises: (a) reactingan aldonic acid hydrazine-5-oxime or alkylimine with a reducing agent inan organic solvent at a temperature between about 20 and 80° C. toproduce the 1,5imino hexitol in a reaction mixture; and (b) separatingthe 1,5-imino hexitol from the reaction mixture.
 28. The process ofclaim 27 wherein the ester and lactam have an arabinosteroconfiguration.
 29. The process of claim 27 wherein the lactam has axylo steroconfiguration.
 30. The process of claim 27 as the alkylimine.31. The process of claim 27 as the oxime. 32.Methyl-2,3,4,6-tetra-0-acetyl-L-arabino-5-hexulosonic acid oxime. 33.Methyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime. 34.Tri-O-acetyl-5-amino-5,6-dideoxy-D-gluconic acid lactam. 35.Methyl-2,3,4,6-tetra-O-acetyl-L-xylo-5-hexulosonic acid hydrazide oxime.36. L-xylo-5-hexulosonic acid hydrazide.